Abstract Methamphetamine is one of the most commonly abused illicit drugs in the United States. Methamphetamine use is most prevalent among adults 18 ? 34 years of age. Notably, this age group includes women of childbearing age. Most studies of prenatal exposure to methamphetamine have focused on neurological outcomes. In contrast, the impact of prenatal exposure to methamphetamine on the adult cardiovascular system has been virtually ignored. In addition, most studies examining the impact of methamphetamine on the heart have focused on acute effects in subjects that were current or recent users of the drug. Few studies have investigated the long term cardiovascular impact of methamphetamine in people or animals that have a history of methamphetamine exposure (prenatal or during adulthood) but are no longer using methamphetamine. Recent work demonstrated that exposure to methamphetamine during the prenatal period or during early adulthood causes sex-dependent changes to the ischemic heart. Female rats, but not their male siblings, that were exposed to methamphetamine prenatally or during early adulthood develop myocardial hypersensitivity to ischemic injury. Furthermore, hypersensitivity to ischemia persists following a period of abstinence from the drug, indicating that methamphetamine may induce sex dependent changes in the heart that are irreversible. These data suggest that women who have heart attacks may be at risk of more extensive myocardial injury if they were exposed to methamphetamine during the prenatal period or during early adulthood, even if they have remained abstinent from the drug for a prolonged period of time. Although methamphetamine use is most prevalent in young adults, heart attacks most frequently occur in the elderly population. Thus, Aim 1 of this study is to determine whether sensitization to ischemic injury following either prenatal or early adult exposure to methamphetamine persists into the geriatric phase of life when ischemic heart disease is most common. Aim 2 is to identify the gestational period of vulnerability to this effect of prenatal methamphetamine. Aim 3 is to identify the mechanism by which methamphetamine causes sex-dependent hypersensitivity to ischemic injury. Ischemic heart disease is the leading cause of death in the United States. In light of the prevalence of methamphetamine abuse, it is critical that we understand the impact of prenatal or early adult exposure to methamphetamine on the ischemic heart, including the long term effects that persist in subjects who have stopped using methamphetamine. We anticipate that the proposed work will advance our understanding of the cardiac consequences of prenatal or adult exposure to methamphetamine. These data will also provide insight into methamphetamine induced changes in gene expression that may underlie methamphetamine-induced cardiomyopathy, arrhythmias, and other cardiac pathologies that result from methamphetamine abuse.